Periodontal disease is one of the most common human diseases afflicting 15% of the population. Recent data has implicated periodontitis as a causative disease for many other systemic complications. Porphoromonas gingivalis is named one of the most virulent periodontopathogens and an etiological agent in the progression of this disease. It also is present in the oral cavity in the absence of the disease. Although the interaction of the bacterium with the host is of major importance for the understanding of the disease mechanisms, both the host as well as the pathogen components involved in the interaction remain poorly understood. In vitro studies have revealed that P. gingivalis can invade a variety of cell types including gingival epithelial cells. It has also been demonstrated to prevent apoptosis in these cells, replicate, and disseminate to surrounding cells. Interestingly, P. gingivalis has been shown to perform these activities in both healthy and susceptible hosts. Studies have also reveled the complex nature of P. gingivalis due to varying results according to, and closely associated with; the host cell type, bacterial strain, initial inoculation, and the use of live (metabolically active) versus dead bacteria, or the presence of specific bacterial components (e.g. cysteine proteinases, LPS). Several studies have focused on the host cell responses mediated by Toll-like receptors challenged with bacterial components to gain insight on the initiation of the innate immune response. Of these bacterial components, little attention has been paid to DNA, especially in oral epithelial cells. To further understand the pathogenesis of P. gingivalis, we will be focusing on one bacterial component, DNA. The specific aims of this study include: (1) The characterization of the response of two oral epithelial cell lines and primary cells harvested from two patients to challenge with P. gingivalis W83 DNA, (2) The role of TLR9 in mediating this response, and (3) other DNA receptors that may play a role in this interaction. Initial in vitro studies revealed that the oral epithelial cell line HN4 responds to challenge with DNA derived from P. gingivalis with gene regulation at the transcriptional level. In addition, we have demonstrated that HN4 cells uptake CpG oligonucleotides. An additional preliminary study has shown that gene regulation does not seem to be significantly impacted in TLR9 knockdown HN4 cell lines that were challenged with P. gingivalis DNA, therefore, we plan to examine the cytosolic DNA receptor DAI, which also may play a role in the pathogenesis of P. gingivalis. Public health Relevance: This study will lead to a greater understanding of the mechanisms of the host response that contribute to the pathogenesis of P. gingivalis W83. These studies may then reveal potential targets for preventing the initiation of periodontal disease.